Central nervous system (CNS) tumors include tumors present in the brain, spinal cord, or the lining around such structures (e.g., meninges and Schwann cells) or eye. Tumors of the CNS may be categorized as primary CNS tumors or secondary CNS tumors. Primary CNS tumors are neoplasms that originate in the CNS. Secondary CNS tumors, the most common form of brain tumors, originate outside of the CNS and result from the primary tumor metastasizing to the CNS. Secondary CNS tumors can either involve the brain directly (i.e., parenchymal involvement) or involve the lining (i.e., leptomeningeal and meningeal involvement). In adults, solid tumors that have been shown to frequently metastasize to the CNS include lung, breast, adenocarcinoma of unknown primary site, melanoma, renal, and colon cancer. In children, primary solid tumors that more commonly metastasize to the CNS include sarcoma, Wilm's tumor, neuroblastoma, and germ cell tumor. In addition to solid tumors, haematological malignancies that can metastasize to the CNS include acute lymphoblastic leukemia, high grade non-Hodgkin's lymphoma, and less commonly acute myeloid leukemia.
Treatment of primary and secondary CNS tumors depends on the multiplicity, location, and grade of the tumor. Treatment of secondary CNS tumors may also depend upon the status of the systemic tumor. Treatment may include any of surgical resection, stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT) and chemotherapy or some combination thereof. Treatment of brain tumors faces a unique challenge compared to other types of cancers, due to the fact that not only are they developed within bone-covered structures, thereby having restricted space to expand, but they are also embedded deeply within an organ carrying a multitude of vital functions. Therefore, even a benign tumor can be life-threatening if it is in an area of the brain that controls critical body functions such as breathing or blood circulation. Treatment normally begins with surgical resection and then follows with radiation or chemotherapy. Surgery faces the risk of removing surrounding tissues that may carry vital brain functions, while radiation and chemotherapy can both harm normal tissues that are near or along the treatment path. Indeed, surgery usually is not recommended if the tumor is in regions of cerebral hemispheres that control speech, vision, movement or cognition. In addition, the use of radiation on children under the age of three is often prohibited because this is a critical time period of brain development. Efficacy of chemotherapy is somewhat limited due to frequent limited duration of effects and lack of targeting and selectivity of the drugs.
The inability of many conventional chemotherapeutic agents to cross the blood-brain barrier (BBB) has historically limited their use in the treatment of CNS tumors. The BBB is formed by the complex tight junctions between the endothelial cells of the brain capillaries and their low endocytic activity (Potschka et al., Journal of Pharm. and Exp. Therapeutics 306(1):124-131, 2003 July). This results in a capillary wall that behaves as a continuous lipid bilayer and prevents the passage of polar and lipid-insoluble substances. Additionally, ATP-dependent multidrug transporters such as P-glycoprotein (Pgp; ABCB1) and multidrug resistance protein MRP2 (ABCC2), which are found in the membranes of brain capillary endothelial cells, are thought to play an important role in BBB function by limiting drug penetration into the brain. It is, therefore, an obstacle to drugs that may combat diseases affecting the CNS.